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BCAA insufficiencies lead to premature ovarian insufficiency via ceramide induced elevation of ROS

ABSTRACT: Premature ovarian insufficiency (POI) is a disease featured by early menopause before 40 years of age, accompanied by an elevation of follicle-stimulating hormone (FSH). Though POI affects many aspects of women’s health, its major causes remain unknown. Many clinical studies have shown that POI patients are generally underweight, indicating a potential correlation between POI and metabolic disorders. To understand the pathogenesis of POI, we performed metabolomics analysis on serum and identified branch chain amino acid (BCAA) insufficiency related metabolic disorders in two independent cohorts from two clinics. A low BCAA diet phenotypically reproduced the metabolic, endocrine, ovarian, and reproductive changes of POI in young C57 B6 mice. A mechanism study revealed that the BCAA insufficiency induced POI is associated with abnormal activation of the ceramide-ROS axis and consequent impairment of ovarian granulosa cell function. Significantly, dietary supplement of BCAA prevented the development of ROS-induced POI in female mice. The results of this pathogenic study will lead to the development of specific therapies for POI.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE215358 | GEO | 2023/03/28

REPOSITORIES: GEO

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BCAA insufficiencies lead to premature ovarian insufficiency via ceramide induced elevation of ROS

Project description:Premature ovarian insufficiency (POI) is a disease featured by early menopause before 40 years of age, accompanied by an elevation of follicle-stimulating hormone (FSH). Though POI affects many aspects of women’s health, its major causes remain unknown. Many clinical studies have shown that POI patients are generally underweight, indicating a potential correlation between POI and metabolic disorders. To understand the pathogenesis of POI, we performed metabolomics analysis on serum and identified branch chain amino acid (BCAA) insufficiency related metabolic disorders in two independent cohorts from two clinics. A low BCAA diet phenotypically reproduced the metabolic, endocrine, ovarian, and reproductive changes of POI in young C57 B6 mice. A mechanism study revealed that the BCAA insufficiency induced POI is associated with abnormal activation of the ceramide-ROS axis and consequent impairment of ovarian granulosa cell function. Significantly, dietary supplement of BCAA prevented the development of ROS-induced POI in female mice. The results of this pathogenic study will lead to the development of specific therapies for POI.

2022-10-13 | PXD037353 | iProX

HO-1 modulates ferroptosis via ROS-mediated mitochondrial dysfunction in cyclophosphamide -induced ovarian granulosa cells

Project description:Abnormal granulosa cells (GCs) death contributes to cyclophosphamide (CTX) -induced primary ovarian insufficiency (POI). To investigate the contribution of GCs in POI, gene profiles of GCs exposed to CTX were assessed using RNA-Seq and bioinformatics analysis. The results showed the differentially expressed genes (DEGs) are enriched in ferroptosis-related pathway, which is correlated with the upregulated Heme oxygenase 1 (HO-1) and downregulated glutathione peroxidase-4 (GPX4). Using CTX-induced cell culture (COV434 and KGN cells), the levels of iron, reactive oxygen species (ROS), lipid peroxide, mitochondrial superoxide, mitochondrial morphology and mitochondrial membrane potential (MMP) were detected by DCFDA, MitoSOX, C11-BODIPY, MitoTracker, Nonylacridine Orange (NAO), JC-1 and transmission electron microscopy respectively. The results showed that iron overload and disrupting ROS, including cytoROS, mtROS and lipROS homeostasis by HO-1 upregultion could induce ferroptosis via mitochondrial dysfunction in CTX-induced GCs. Moreover, HO-1 inhibition could suppress ferroptosis induced GPX4 depletion. This implies the role of ROS in CTX-induced ferroptosis and highlighted the effect of HO-1 modulators of improving CTX-induced ovarian damage, which may provide a theoretical basis for preventing or restoring GC and ovarian function in patients with POI.

2023-10-30 | GSE243720 | GEO

Identify urinary exosome microRNAs that are unique to premature ovarian insufficiency

Project description:This study is to identify urinary exosome microRNAs (miRNAs) that are unique to premature ovarian insufficiency (POI) with and without Turner syndrome and to use them as diagnostic markers for POI patients. We examined the miRNAexpression profile in urine exosomes from POI patients with and without Turner syndrome.

2022-09-28 | GSE205700 | GEO

Homozygosity mapping in family segregating premature ovarian insufficiency (POI)

Project description:Premature ovarian insufficiency (POI) is defined as a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 (secondary amenorrhea) with hypergonadotropism and hypoestrogenism. Premature ovarian insufficiency has few known genetic causes but in familial cases a genetic link is often suspected. A large consanguineous family with three female affected with POI was investigated. All samples including 3 affected and 5 unaffecd underwent whole genome SNP genotyping using Affymetric Axiom_GW_Hu_SNP array. Linkage analysis was carried out using HomozygosityMapper and Allegro softwares.Linkage analysis mapped the disease phenotype to long arm of chromosome 20. Sequence data analysis of potential candidate genes failed to detect any pathogenic variant.

2014-03-20 | GSE56043 | GEO

T&T-seq Reveals Impaired Translation Regulation Abilities of POI-associated EIF4ENIF1 Mutations

Project description:Premature Ovarian Insufficiency (POI) refers to the decline and stagnation of ovarian function in women before the age of 40.POI-associated EIF4ENIF1 mutations and the distribution of functional domains in the EIF4ENIF1 protein have been separately described. However, not all the clinically observed EIF4ENIF1 mutations in POI cases fall in clearly defined functional domains of the EIF4ENIF1 protein. Herein, we introduce T&T seq as a new evaluation tool to sensitively measure the translation regulation capacities of EIF4ENIF1 proteins with clinically discovered mutations. The sequencing results showed that POI-associated EIF4ENIF1 mutations impaired its translation repression function to different degrees.

2024-04-09 | GSE240761 | GEO

RNA-Seq Facilitates Quantitative Analysis of Wild Type and Bnc1tr/tr ovary Transcriptomes

Project description:Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles. POI causes infertility, serious daily life disturbances and long-term health risks. However, the underlying mechanism remains largely unknown. We have previously identified Basonuclin1 (BNC1) mutation from a large Chinese POI pedigree and find the targeted Bnc1 mutation mouse exhibites POI. In this study, we find that BNC1 plays a key role in the dynamic balance of ovarian reserve, and maintaining lipid metabolism and redox homeostasis in oocytes during follicular development. Deficiency of BNC1 results in premature follicular activation and accelerated follicular atresia, but doesn’t affect the ovarian primordial follicle reserve. Mechanistically, BNC1 targets the NF2-YAP pathway to trigger oocyte ferroptosis. Inhibition of ferroptosis significantly rescues POI. These findings uncover a novel pathologic mechanism of POI based on BNC1 deficiency and is the first report showing ferroptosis involved in oocyte death.

2022-08-31 | GSE194196 | GEO

Genome-wide maps of chromatin state in Wild Type mouse ovary

2022-08-31 | GSE194195 | GEO

RNA-Seq Facilitates Quantitative Analysis of Wild Type and Bnc1tr/tr oocyte Transcriptomes

2022-08-31 | GSE194194 | GEO

Comparison of the therapeutic effects between stem cells and exosomes in primary ovarian insufficiency: As promising as cells but different persistency and dosage.

Project description:Primary ovarian insufficiency (POI) refers to the loss of ovarian function under the age of 40 and results in amenorrhea and infertility. Our previous studies have shown that transplantation of mesenchymal stem cells (MSCs) and MSC-derived exosomes in chemotherapy-induced POI mouse ovaries can reverse the POI and eventually achieve pregnancy. Based on our recent studies, MSC-derived exosomes have almost equal therapeutic potentials as transplanted MSCs. However, it is still unclear whether exosomes can completely replace MSCs in POI treatment. In this study, we induced POI in C57/BL6 mice by chemotherapy (CXT) using a standard protocol. We compared the RNA expression pattern in ovarian tissue after MSC or exosome treatment. our data suggest that a minimal 10-fold increase, and ideally 100-fold increase, in the exosome concentration is required to generate more analogous results to MSC treatment.

2023-05-30 | GSE233743 | GEO

BCAA catabolic mutants in prolonged darkness

Project description:We used RNA-Seq to ask whether the transcripts for the proposed BCKDH subunits are upregulated in wild-type plants subjected to prolonged darkness. These experiments were performed using rosette leaves from 5-week-old, short-day-grown (8h light/16h dark) Col-0 wild-type plants moved to constant darkness for 6h, 24h, 48h and 72h, and grown in short day for 72h as control. The transcripts of eight BCAA catabolism genes were increased nine- to 400-fold within the first 6h of prolonged darkness, and remained high until the last time point. These results are consistent with the hypothesis that BCAA catabolic enzymes - including BCKDH subunits E1A1, E1B1, E1B2 and E2 - have one or more physiological roles in the dark. Rosette leaf mRNA profiles of 5-week old Col wild type (WT, CS60000) and BCAA catabolic mutants ivd1-2 and hml1-2 were generated byRNA sequencing, in duplicate, using Illumina HiSeq2500.

2015-04-16 | E-GEOD-67956 | biostudies-arrayexpress

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